RAS模拟小分子Rigosertib联合西妥昔单抗治疗RAS突变型结直肠癌的作用及机制研究

抗EGFR的西妥昔单抗是治疗RAS野生型结直肠癌的有效药物，但对RAS突变型结直肠癌无效。西妥昔单抗联合RAS信号通路抑制剂的治疗方案有望解决此问题。Rigosertib（RGS）能模拟RAS与其下游效应蛋白结合，从而阻断RAS信号通路。我们前期研究发现RGS通过抑制增殖和促进凋亡显著杀伤RAS突变型结直肠癌细胞，小鼠移植瘤（PDX）模型实验也证实RGS对RAS突变型结肠癌有抗癌能力。我们注意到RGS虽能有效抑制RAS信号通路，但反馈激活EGFR下游其他信号通路。据此推测联用西妥昔单抗和RGS抑制EGFR和RAS信号通路，将是治疗RAS突变型结直肠癌的有效方案。本研究将利用皮下成瘤模型、半脾肝转移动物模型和PDX模型验证二者联合干预价值，并通过磷酸化蛋白质谱、免疫印迹、免疫组化等手段分析二者联合对EGFR下游各信号通路的抑制情况。本研究有望为提高RAS突变型结直肠癌的疗效提供新的解决方案。

Cetuximab which targeted the epidermal growth factor receptor (EGFR) had proven to be efficacious in RAS wild-type colorectal cancers, but its effect was limited in RAS-mutant colorectal cancer. Combined treatment of Cetuximab and RAS down-stream signaling inhibitors was supposed to be a promising therapeutic method. Rigosertib (RGS) which was reported to be RAS-mimetic small molecule could bind to the RAS-binding domains (RBDs) of RAS effectors, and then blocked the RAS-signaling. In our previous work, RGS showed anti-proliferative and pro-apoptotic effects in RAS-mutant colorectal cancer cells; RGS also inhibited growth of Patient-derived Tumor Xenograft (PDX) in nude mice. We found that RGS could block the RAS down-stream signaling, however, its inhibition of RAS signaling induced feedback activation of other EGFR down-stream signaling. We supposed that the combined treatment of Rigosertib and Cetuximab could block the EGFR and RAS signaling pathway, which might be a therapeutic strategy in RAS-mutant colorectal cancer. In our research, we will verify its curative effects in colorectal cancer subcutaneous tumor xenograft model, hemi-splenic liver metastasis model, and patient-derived tumor xenograft model; then, we will analyze its effect in EGFR down-stream signaling pathway by phosphorylated protein mass spectrometry, western blot and immunohistochemistry.